Mycobacterium tuberculosis alters the metabolism of alternatively activated macrophages making them foamy cells

JOSÉ LUIS MARÍN FRANCO; FERREYRA, MALENA; FUENTES, FEDERICO; BARRIONUEVO, PAULA; COUGOULE, CÉLINE; MARÍA DEL CARMEN SASIAIN; MAIO, MARIANO; EDUARDO JOSÉ MORAÑA; LÓPEZ, BEATRIZ; NEYROLLES, OLIVIER; VÉROLLET, CHRISTEL; BALBOA, LUCIANA; MELANIE GENOULA; DOLOTOWICZ, BELÉN; DOMINGO PALMERO; MILILLO, MARÍA AYELÉN; MASCARAU, RÉMI; GEANNCARLO LUGO-VILLARINO

Santa Fe, Nuevo Mexico

Simposio; Keystone Symposia Conference A2: Tuberculosis: Immunity and Immune Evasion; 2020

Keystone Symposia

The ability of Mycobacterium tuberculosis (Mtb) to persist inside the host relies on metabolic adaptations, such as the accumulation of lipid bodies in the foamy macrophages (FM). The activation state of macrophages is tightly associated to different metabolic pathways, especially to lipids handling, but whether differentiation towards FM differs between macrophage profiles remains unclear. Here, we aimed to elucidate whether different activation/metabolic programs in human macrophages exposed to a genuine tuberculosis (TB)-associated microenvironment differ in their ability to form FM, and how it impacts on the control of infection. We showed that M(IL-4) macrophages prevents FM formation induced by the pleural effusion from TB patients. In these cells, lipid bodies are quickly disrupted by lipolysis and released fatty acids enter the β-oxidation pathway, ultimately fueling the mitochondrial generation of ATP. We demonstrated that inhibiting the lipolytic activity or β-oxidation drives M(IL-4) macrophages into FM. Also, alveolar macrophages, that have a predominant oxidative metabolism, are less prone to become FM compared to bone marrow derived-macrophages. Upon Mtb infection, M(IL-4) macrophages are metabolically re-programmed towards the aerobic glycolytic pathway as well as the formation of FM, phenotype which could be prevented either by fostering β-oxidation or inhibiting glycolytic pathway induced by HIF-1α. In conclusion, our results evidence for a role of STAT6 driven-fatty acids β-oxidation in preventing FM differentiation, and reveal a counterattack mechanism by Mtb throughout the induction of HIF-1α in M(IL-4) macrophages, making them foamy.